Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder characterized by cyst formation in ductal organs, principally the kidneys and liver, vascular aneurysms, cardiac valve defects and colonic diverticulae. The disease commonly leads to progressive renal insufficiency in adult life, but can occasionally present in childhood. In the US, ADPKD is the fourth leading cause of chronic renal failure requiring hemodialysis or transplantation, and costs 750 million dollars annually. The cause of renal cyst formation in ADPKD is unknown. Studies using human kidneys with cystic disease and a number of animal models of cystogenesis have identified abnormalities in epithelial cell proliferation, secretion and basement membrane composition as contributing factors, but failed to identify the primary abnormality. Genetic studies have linked the defect in the majority of patients with ADPKD to a single locus on chromosome 16. More recently, the defective protein, PKD1 was identified and fully sequenced. The primary sequence of PKD1 reveals a unique compilation of known domains that are likely to be involved in protein-protein and protein-carbohydrate recognition events. PKD1 is also predicted to span the plasma membrane several times. In this application, we propose to study the structure and function of PKD1. Our first specific aim is to generate PKD1 knockout mice and to determine through a serial analysis, the morphologic changes taking place in kidneys from PKD1 knockout mice that lead to cystogenesis, studies that were not possible in humans with ADPKD. Second, we propose to studs the cell and subcellular distribution of PKD1 and determine its topology in the plasma membrane. Third, we will attempt to .elucidate the cellular function(s) of PKD1 using kidney organ- and cell cultures derived from normal and null mice and function blocking antibodies to specific domains in PKD1. Molecular-, biochemical and cell biology techniques will be used. The generation of a mouse model for PKD1 will be valuable in testing future potential therapies for this disease. Furthermore, since the cellular aberrations expressed in cystic epithelia appear to be normally displayed by differentiating and regenerating epithelium during morphogenesis and wound healing respectively, an understanding of the function(s) of PKD1 in cystogenesis may also shed valuable insight on the process of epithelial morphogenesis, nephrogenesis and the renal response to injury.